An experimental therapy for mania associated with bipolar disorder could improve treatment for the disease while also illuminating the mechanism of action of conventional lithium treatment. Though it's effective, lithium's toxicity and lack of selectivity cause unpleasant side effects that reduce patient usage. Alan P. Kozikowski of the University of Illinois, Chicago; Paul McGonigle of PsychoGenics, a drug discovery firm in Tarrytown, N.Y.; and colleagues used structure-based design to develop small-molecule substitutes for lithium (J. Am. Chem. Soc., DOI: 10.1021/ja068969w). The compounds selectively deactivate the enzyme glycogen synthase kinase-3β (GSK-3β), thought to be one of lithium's multiple targets. The researchers say their new compounds are the first selective GSK-3β inhibitors capable of crossing the blood-brain barrier. This property enabled the team to assess the therapeutic potential of targeting GSK-3β for mania. In fact, the researchers found that their best drug lead controls mania in a mouse model of the disorder.